Hypogonadotropic hypogonadism 6 with or without anosmia

Summary

Hypogonadotropic hypogonadism 6 with or without anosmia (MONDO:0012988) is a disease caused by FGF8 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: FGF8 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 6 with or without anosmia
Mondo ID	MONDO:0012988
MeSH	C567199
OMIM	612702
DOID	DOID:0090086
UMLS	C3552574
MedGen	765488
GARD	0010774
Is cancer (heuristic)	no

Also known as: FGF8 hypogonadotropic hypogonadism · HH6 · hypogonadotropic hypogonadism 6 with or without anosmia · hypogonadotropic hypogonadism caused by mutation in FGF8 · KAL6 · Kallmann syndrome 6

Data availability: 24 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Kallmann syndrome › hypogonadotropic hypogonadism 6 with or without anosmia

Related subtypes (17): hypogonadotropic hypogonadism 2 with or without anosmia, hypogonadotropic hypogonadism 3 with or without anosmia, hypogonadotropic hypogonadism 1 with or without anosmia, hypogonadotropic hypogonadism 4 with or without anosmia, hypogonadotropic hypogonadism 5 with or without anosmia, hypogonadotropic hypogonadism 8 with or without anosmia, hypogonadotropic hypogonadism 9 with or without anosmia, hypogonadotropic hypogonadism 11 with or without anosmia, hypogonadotropic hypogonadism 14 with or without anosmia, hypogonadotropic hypogonadism 15 with or without anosmia, hypogonadotropic hypogonadism 16 with or without anosmia, hypogonadotropic hypogonadism 17 with or without anosmia, hypogonadotropic hypogonadism 18 with or without anosmia, hypogonadotropic hypogonadism 19 with or without anosmia, hypogonadotropic hypogonadism 20 with or without anosmia, hypogonadotropic hypogonadism 21 with or without anosmia, hypogonadotropic hypogonadism 22 with or without anosmia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

24 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 5 conflicting classifications of pathogenicity, 5 pathogenic, 2 benign, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
235082	NM_033163.5(FGF8):c.385C>T (p.Arg129Ter)	FGF8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
599013	NM_033163.5(FGF8):c.379C>T (p.Arg127Ter)	FGF8	Pathogenic	criteria provided, single submitter
9121	NM_033163.5(FGF8):c.40C>A (p.His14Asn)	FGF8	Pathogenic	no assertion criteria provided
9123	NM_033163.5(FGF8):c.118T>C (p.Phe40Leu)	FGF8	Pathogenic	no assertion criteria provided
9124	NM_033163.5(FGF8):c.298A>G (p.Lys100Glu)	FGF8	Pathogenic	no assertion criteria provided
9125	NM_033163.5(FGF8):c.379C>G (p.Arg127Gly)	FGF8	Pathogenic	no assertion criteria provided
235081	NM_033163.5(FGF8):c.356C>T (p.Thr119Met)	FGF8	Likely pathogenic	criteria provided, multiple submitters, no conflicts
435185	NM_033163.5(FGF8):c.628_629dup (p.His211fs)	FGF8	Likely pathogenic	criteria provided, single submitter
140613	NM_033163.5(FGF8):c.237C>G (p.Leu79=)	FGF8	Conflicting classifications of pathogenicity	no assertion criteria provided
4081393	NM_033163.5(FGF8):c.379del (p.Arg127fs)	FGF8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
545463	NM_033163.5(FGF8):c.86_103dup (p.Gly29_Arg34dup)	FGF8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9122	NM_033163.5(FGF8):c.77C>T (p.Pro26Leu)	FGF8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9126	NM_033163.5(FGF8):c.686C>T (p.Thr229Met)	FGF8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031556	NM_033163.5(FGF8):c.335_337+2del	FGF8	Uncertain significance	criteria provided, single submitter
140612	NM_033163.5(FGF8):c.451G>A (p.Gly151Ser)	FGF8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1708951	NM_033163.5(FGF8):c.278A>G (p.His93Arg)	FGF8	Uncertain significance	criteria provided, single submitter
3238944	NM_033163.5(FGF8):c.195G>C (p.Val65=)	FGF8	Uncertain significance	criteria provided, single submitter
3238945	NM_033163.5(FGF8):c.157-14T>C	FGF8	Uncertain significance	criteria provided, single submitter
3278656	NM_033163.5(FGF8):c.439G>A (p.Ala147Thr)	FGF8	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779653	NM_033163.5(FGF8):c.141G>C (p.Gln47His)	FGF8	Uncertain significance	criteria provided, multiple submitters, no conflicts
4538421	NM_033163.5(FGF8):c.656G>A (p.Arg219His)	FGF8	Uncertain significance	no assertion criteria provided
983051	NM_033163.5(FGF8):c.157-6C>G	FGF8	Uncertain significance	criteria provided, single submitter
1271093	NM_033163.5(FGF8):c.444+19G>A	FGF8	Benign	criteria provided, multiple submitters, no conflicts
218825	NM_033163.5(FGF8):c.445-62G>A	FGF8	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FGF8	Strong	Autosomal dominant	hypogonadotropic hypogonadism 6 with or without anosmia	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGF8	Orphanet:220386	Semilobar holoprosencephaly
FGF8	Orphanet:280195	Septopreoptic holoprosencephaly
FGF8	Orphanet:280200	Microform holoprosencephaly
FGF8	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
FGF8	Orphanet:478	Kallmann syndrome
FGF8	Orphanet:93924	Lobar holoprosencephaly
FGF8	Orphanet:93925	Alobar holoprosencephaly
FGF8	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FGF8	HGNC:3686	ENSG00000107831	P55075	Fibroblast growth factor 8	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGF8	Fibroblast growth factor 8	Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGF8	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
metanephric glomerulus	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGF8	109	tissue_specific	yes	primordial germ cell in gonad, metanephric glomerulus, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGF8	4,536

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGF8	P55075	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FGFR3b ligand binding and activation	1	1631.4×	0.003	FGF8
Formation of the posterior neural plate	1	1142.0×	0.003	FGF8
Signaling by activated point mutants of FGFR1	1	951.7×	0.003	FGF8
Signaling by activated point mutants of FGFR3	1	951.7×	0.003	FGF8
FGFR3c ligand binding and activation	1	878.5×	0.003	FGF8
FGFR2c ligand binding and activation	1	878.5×	0.003	FGF8
Phospholipase C-mediated cascade; FGFR3	1	878.5×	0.003	FGF8
FGFRL1 modulation of FGFR1 signaling	1	878.5×	0.003	FGF8
FGFR4 ligand binding and activation	1	815.7×	0.003	FGF8
FGFR1c ligand binding and activation	1	761.3×	0.003	FGF8
Phospholipase C-mediated cascade; FGFR4	1	761.3×	0.003	FGF8
Activated point mutants of FGFR2	1	671.8×	0.003	FGF8
Phospholipase C-mediated cascade: FGFR1	1	671.8×	0.003	FGF8
Phospholipase C-mediated cascade; FGFR2	1	634.4×	0.003	FGF8
PI-3K cascade:FGFR3	1	634.4×	0.003	FGF8
SHC-mediated cascade:FGFR3	1	601.0×	0.003	FGF8
PI-3K cascade:FGFR4	1	571.0×	0.003	FGF8
Downstream signaling of activated FGFR1	1	543.8×	0.003	FGF8
FRS-mediated FGFR3 signaling	1	543.8×	0.003	FGF8
SHC-mediated cascade:FGFR4	1	543.8×	0.003	FGF8
PI-3K cascade:FGFR1	1	519.1×	0.003	FGF8
SHC-mediated cascade:FGFR1	1	496.5×	0.003	FGF8
PI-3K cascade:FGFR2	1	496.5×	0.003	FGF8
FRS-mediated FGFR4 signaling	1	496.5×	0.003	FGF8
Signaling by FGFR3 in disease	1	496.5×	0.003	FGF8
SHC-mediated cascade:FGFR2	1	475.8×	0.003	FGF8
FRS-mediated FGFR1 signaling	1	456.8×	0.003	FGF8
FRS-mediated FGFR2 signaling	1	439.2×	0.003	FGF8
Negative regulation of FGFR3 signaling	1	439.2×	0.003	FGF8
Negative regulation of FGFR4 signaling	1	407.9×	0.003	FGF8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pallium development	1	16852.0×	0.001	FGF8
midbrain-hindbrain boundary development	1	8426.0×	0.001	FGF8
negative regulation of cardiac muscle tissue development	1	8426.0×	0.001	FGF8
cell migration involved in mesendoderm migration	1	8426.0×	0.001	FGF8
larynx morphogenesis	1	8426.0×	0.001	FGF8
neural plate morphogenesis	1	5617.3×	0.001	FGF8
subpallium development	1	5617.3×	0.001	FGF8
corticotropin hormone secreting cell differentiation	1	5617.3×	0.001	FGF8
dorsal/ventral axon guidance	1	4213.0×	0.002	FGF8
mesodermal cell migration	1	3370.4×	0.002	FGF8
thyroid-stimulating hormone-secreting cell differentiation	1	2808.7×	0.002	FGF8
mitotic nuclear division	1	2808.7×	0.002	FGF8
forebrain neuron development	1	2407.4×	0.002	FGF8
regulation of odontogenesis of dentin-containing tooth	1	2407.4×	0.002	FGF8
forebrain dorsal/ventral pattern formation	1	2106.5×	0.002	FGF8
otic vesicle formation	1	2106.5×	0.002	FGF8
embryonic neurocranium morphogenesis	1	1872.4×	0.002	FGF8
mesonephros development	1	1532.0×	0.002	FGF8
neuroepithelial cell differentiation	1	1532.0×	0.002	FGF8
epithelial to mesenchymal transition involved in endocardial cushion formation	1	1404.3×	0.002	FGF8
positive regulation of organ growth	1	1404.3×	0.002	FGF8
forebrain morphogenesis	1	1404.3×	0.002	FGF8
branching involved in salivary gland morphogenesis	1	1404.3×	0.002	FGF8
cell proliferation in forebrain	1	1296.3×	0.002	FGF8
organ induction	1	1203.7×	0.002	FGF8
gonad development	1	1123.5×	0.002	FGF8
positive regulation of G protein-coupled receptor signaling pathway	1	1053.2×	0.002	FGF8
lung morphogenesis	1	1053.2×	0.002	FGF8
male genitalia development	1	887.0×	0.002	FGF8
aorta morphogenesis	1	887.0×	0.002	FGF8

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGF8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FGF8

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FGF8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.